The identification of humans with mutations in PPAR-γ (peroxisome-proliferator-activated receptor-γ) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-γ regulates metabolic processes. Ablation of PPAR-γ in vivo is lethal and thus dissection of PPAR-γ function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-γ impairment and are useful to elucidate how PPAR-γ regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-γ in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-γ regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-γ increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-γ, some murine models suggest PPAR-γ expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-γ that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-γ have provided useful in vivo systems to dissect the function of PPAR-γ, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-γ in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.

The discovery that PPAR-γ (peroxisome-proliferator-activated receptor-γ) is a molecular target of the TZDs (thiazolidinediones), a class of insulin-sensitizing agents, identified this receptor as a key molecular player in the maintenance of energy homoeostasis. PPAR-γ is a member of the nuclear hormone receptor superfamily and is able to promote transcription by binding specific sequences in the promoters of target genes. The natural ligand for PPAR-γ is still unknown; however, there is evidence that small lipophilic substances, such as polyunsaturated fatty acids and fatty acid derivatives (eiocosanoids) [1] bind and activate this receptor. This supports the concept that PPAR-γ is a nutrient sensor whose main role is to finely tune metabolic homoeostasis in the face of different nutritional states. PPAR-γ is transcribed into three splice variants that produce two distinct protein products, PPAR-γ1 that is expressed in many tissues, and PPAR-γ2, which is expressed mainly in white and brown adipose tissue. Evidence from human mutations in PPAR-γ has underlined the importance of PPAR-γ in the development of adipose tissue, in the maintenance of glucose and lipid homoeostasis and more generally in the control of energy balance. Patients harbouring a mutation in the ligand-binding domain of PPAR-γ have a stereotyped phenotype characterized by partial lipodystrophy, severe insulin resistance, dyslipidaemia, hepatic steatosis and hypertension identifying PPAR-γ as one of the main molecular players in the pathogenesis of the metabolic syndrome [2,2a].

The precise mechanism by which activation of PPAR-γ induces specific metabolic responses is not completely understood but in the last few years the use of genetically modified animals has offered a powerful tool to dissect the mechanism of action of PPAR-γ in vivo. Cellular, genetic and pharmacological studies have provided evidence that the insulin-sensitizing effects of PPAR-γ are mainly produced in the adipose tissue [3]. The link between PPAR-γ and glucose homoeostasis may lie in the proadipogenic activity of PPAR-γ. Indeed maintenance of normal glucose homoeostasis requires development of the right amount of adipose tissue as shown by animal models of obesity and lipodystrophy. In addition to its effects in adipogenesis, PPAR-γ activation induces two physiological adaptations in mature adipose tissue that may contribute to improve insulin sensitivity. First, activation of PPAR-γ enhances lipid uptake in adipose tissue promoting the transcription of genes involved in fatty acid uptake and triacylglycerol storage. This fat stealing effect prevents ectopic accumulation of lipid in non-adipose tissues such as liver, skeletal muscle and β-cells. Secondly, activation of PPAR-γ promotes the expression of a proinsulin sensitizing adipokine profile [4]. The phenotype of PPAR-γ-related mouse models have revealed that the insulin-sensitizing effects of PPAR-γ involve complex adaptations mediated by crosstalk between insulin-sensitive organs.

Initial PPAR-γ knockout: complex regulation of PPAR-γ-mediated gene transcription

Initial attempts to generate a PPAR-γ knockout mouse showed that null embryos die at embryonic day 10 from impaired placental development [5]. In the absence of a surviving global PPAR-γ knockout model the heterozygous state was examined in detail. Since PPAR-γ agonism improves insulin sensitivity, it was predicted that a decreased gene dose present in the heterozygous state would worsen insulin resistance. Surprisingly, animals heterozygous for PPAR-γ are more insulin-sensitive compared with wt (wild-type) littermates and these animals are protected from age-induced insulin resistance [6]. Miles et al. [6] explained this phenotype as a result of a lack of transcriptional repression by PPAR-γ; thus in an environment of decreased PPAR-γ protein, repression of gene transcripts normally impairing insulin sensitivity is removed. In support of this, a recent report has identified that unliganded PPAR-γ can associate with co-repressors such that expression of an adipocyte target gene is silenced in the absence of PPAR-γ ligand [7]. Increased leptin expression identified in the PPAR-γ+/− mice has also been suggested to contribute to the amelioration of insulin resistance [6] through its pro-oxidative effects in liver and muscle [8].

Mouse models with partial PPAR-γ inactivation

The generation of mouse models with tissue-specific deletion, isoform-specific deletion and knockin of human dominant negative mutation of PPAR-γ, has provided in vivo models of partial PPAR-γ impairment, helpful to dissect PPAR-γ action and to understand PPAR-γ's role in different organs. Moreover, these animals have demonstrated that PPAR-γ can regulate a complex crosstalk between insulin-sensitive organs. Although phenotypic analysis of the tissue-specific knockout animals has focused mainly on the effects of gene knockout on insulin sensitivity [9], most models also show some impairment of lipid homoeostasis, stressing the importance of PPAR-γ in regulating nutrient sensing and lipid storage.

Tissue-specific ablation of PPAR-γ: dissection of PPAR-γ function in vivo

PPAR-γ determines adipose tissue development and distribution

As mentioned above, PPAR-γ knockout is embryonically lethal and thus the physiological effects of global PPAR-γ deletion could not be examined in adult mice. A subsequent attempt to bypass placental development through tetraploid-rescue using PPAR-γ wt/PPAR-γ null chimaeras, emphasizes the importance of PPAR-γ for normal adipose tissue development as only PPAR-γ+/+ adipocytes were found in the animals [5,10]. Moreover, mice harbouring dominant negative mutations of PPAR-γ show an altered distribution of fat pads revealing a role for PPAR-γ in controlling adipose tissue localization and distribution [11]. Ablation or impaired function of PPAR-γ specifically in adipose tissue results in an insulin-resistant lipodystrophic phenotype. Several groups have used different strategies to develop mouse models with selective loss of PPAR-γ function in adipose tissue (Table 1) [1215]. Although the hypomorphic and the ATKO (adipose tissue-specific knockout mice) showed normal whole body insulin sensitivity when fed a chow diet, they had hepatic insulin resistance [12,13]. A clear interpretation of the role of PPAR-γ in insulin sensitivity in the hypomorphic model is difficult given the overall poor health of the animals and the variable expression of PPAR-γ1 and γ2 isoforms in different tissues. Paradoxically, the hypomorphic PPAR-γ mouse model shows relatively mild impairment of glucose homoeostasis despite the presence of severe lipodystrophy. It has been suggested that this mild phenotype may result from a compensatory response by the skeletal muscle as indicated by induction of genes mediating oxidative metabolism [12]. In the ATKO, adipose tissue is unable to appropriately store lipid and suppress lipolysis and thus when challenged with high-fat feeding leads to persistently elevated serum lipid and lipotoxic infiltration of liver [13]. Subsequently, this mouse model develops whole body insulin resistance due to impaired suppression of gluconeogenesis in liver as a result of the lipotoxic insult. Interestingly, TZD treatment of ATKO mice rescues liver insulin resistance suggesting that PPAR-γ outside adipose tissue can contribute to improve insulin sensitivity. However, TZD treatment did not ameliorate plasma NEFA [non-esterified (free) fatty acid] levels, suggesting that this effect is specific to PPAR-γ activation in adipose tissue [13]. Models of adipose tissue-specific impairment of PPAR-γ function demonstrate that PPAR-γ activity is necessary for normal adipose tissue development and maintenance. Therefore a direct effect of PPAR-γ on insulin-sensitivity independent of its adipose tissue effects is hard to dissect as the severe lipodystrophy of these animals is sure to contribute to the defective glucose homoeostasis of these animals.

Table 1
Summary of the metabolic characterizations of several PPAR-γ mouse models

HFD, high-fat diet; IS, insulin sensitivity; IR, insulin resistance; TG, triacylglycerols.

  Generation of mouse line     Glucose homoeostasis   
Mouse model Reference Strategy Background Lethality Weight Adipose tissue Lipid homoeostasis Whole body Hepatic Muscle TZD Vascular 
Total knockout             
 PPAR-γ−/− [5lacZ-neo in exon 2 C57BL/6-129Sv E10  Tetraploid rescue severe lipodystrophy      Abnormal placental vascularization 
 PPAR-γ+/− [6lacZ-neo in exon 2 C57BL/6-129Sv  ↔ ↔  ↑ IS ↓ Age IR ↔ HFD IR ↑ ↑ Effective  
Tissue specific             
 Mature adipocytes [13aP2-cre C57BL/6J  ↓ HFD Lipodystrophy ↑ NEFA+TG, liver steatosis-HFD HFD IR IR  Partially effective (liver)  
 Mature adipocytes [15aP2-cre C57BL/6J  ↓ HFD Lipodystrophy Liver steatosis, ↑ serum TG ↔ Improved IS Impaired   
 Adipose tissue (adult mice) [14Tamoxifen cre-ER C57BL/6-129SJL   Death of mature adipocytes       
 Hypomorph [12neo cassette 3′ of exon B C57BL/6J, 129Sv and C57BL/6J/129Sv 50% pups ↓ Lipodystrophy Hyperlipidemia Mild glucose intol.     
 Skeletal muscle [18MCK-cre FVB-129Sv-C57BL/6  ↑ HFD ↑ HFD  IR IR ↔ Effective  
 Skeletal muscle [17MCK-cre C57BL/6J  ↔   IR  80% decrease Not effective  
 Liver (ob/ob) [20Albumin-cre × ob/ob C57BL/6-129  ↔  Improved liver steatosis worsened serum lipid ↑ IR     
 Liver [21Albumin-cre FVB/N-129-C57BL/6  ↔ ↑ HFD ↓ Lipid clearance Hyperlipidemia IR-age/HFD ↔  Effective  
 Liver (AZip) [21Albumin-cre × A-ZIP FVB/N-129-C57BL/6  ↔  Improved liver steatosis worsened serum lipid  ↔ Worsened IR Not effective  
 β-Cell [24Rat insulin-cre FVB-129Sv-C57BL/6     B-cell hyperplasia ↔  Effective  
 Macrophage [25MX-cre 129-C57BL/6        Effective Impaired cholesterol efflux 
 Isoform specific PPAR-γ2 [28RFP-PGK-neo inserted in exon B C57BL/6-129Sv  ↔ Lipodystrophic ↓↓ in vitro diff Normal liver Male IR   Effective  
 PPAR-γ2 [29IRESβGalMCNeo inserted in exonB1 C57BL/6-129Sv  ↔ ↓↓ in vitro diff.  Male IR ↔    
 Dominant negative mutation P465L [11P465L knockin C57BL/6-129Sv Homozygous lethal ↔ Redistribution  ↔ ↔ ↔  Hypertension 
 L466A [30L466A knockin 129Sv/J Homozygous lethal ↓ Smaller adipocytes ↑ NEFA, liver steatosis IR-HFD  IR-HFD  Hypertension, female 
  Generation of mouse line     Glucose homoeostasis   
Mouse model Reference Strategy Background Lethality Weight Adipose tissue Lipid homoeostasis Whole body Hepatic Muscle TZD Vascular 
Total knockout             
 PPAR-γ−/− [5lacZ-neo in exon 2 C57BL/6-129Sv E10  Tetraploid rescue severe lipodystrophy      Abnormal placental vascularization 
 PPAR-γ+/− [6lacZ-neo in exon 2 C57BL/6-129Sv  ↔ ↔  ↑ IS ↓ Age IR ↔ HFD IR ↑ ↑ Effective  
Tissue specific             
 Mature adipocytes [13aP2-cre C57BL/6J  ↓ HFD Lipodystrophy ↑ NEFA+TG, liver steatosis-HFD HFD IR IR  Partially effective (liver)  
 Mature adipocytes [15aP2-cre C57BL/6J  ↓ HFD Lipodystrophy Liver steatosis, ↑ serum TG ↔ Improved IS Impaired   
 Adipose tissue (adult mice) [14Tamoxifen cre-ER C57BL/6-129SJL   Death of mature adipocytes       
 Hypomorph [12neo cassette 3′ of exon B C57BL/6J, 129Sv and C57BL/6J/129Sv 50% pups ↓ Lipodystrophy Hyperlipidemia Mild glucose intol.     
 Skeletal muscle [18MCK-cre FVB-129Sv-C57BL/6  ↑ HFD ↑ HFD  IR IR ↔ Effective  
 Skeletal muscle [17MCK-cre C57BL/6J  ↔   IR  80% decrease Not effective  
 Liver (ob/ob) [20Albumin-cre × ob/ob C57BL/6-129  ↔  Improved liver steatosis worsened serum lipid ↑ IR     
 Liver [21Albumin-cre FVB/N-129-C57BL/6  ↔ ↑ HFD ↓ Lipid clearance Hyperlipidemia IR-age/HFD ↔  Effective  
 Liver (AZip) [21Albumin-cre × A-ZIP FVB/N-129-C57BL/6  ↔  Improved liver steatosis worsened serum lipid  ↔ Worsened IR Not effective  
 β-Cell [24Rat insulin-cre FVB-129Sv-C57BL/6     B-cell hyperplasia ↔  Effective  
 Macrophage [25MX-cre 129-C57BL/6        Effective Impaired cholesterol efflux 
 Isoform specific PPAR-γ2 [28RFP-PGK-neo inserted in exon B C57BL/6-129Sv  ↔ Lipodystrophic ↓↓ in vitro diff Normal liver Male IR   Effective  
 PPAR-γ2 [29IRESβGalMCNeo inserted in exonB1 C57BL/6-129Sv  ↔ ↓↓ in vitro diff.  Male IR ↔    
 Dominant negative mutation P465L [11P465L knockin C57BL/6-129Sv Homozygous lethal ↔ Redistribution  ↔ ↔ ↔  Hypertension 
 L466A [30L466A knockin 129Sv/J Homozygous lethal ↓ Smaller adipocytes ↑ NEFA, liver steatosis IR-HFD  IR-HFD  Hypertension, female 

Skeletal muscle-derived PPAR-γ contributes to the regulation of glucose homoeostasis

Skeletal muscle represents the principal target of insulin in terms of glucose disposal and thus small changes in muscle insulin-sensitivity impact significantly on whole body glucose homoeostasis. Although PPAR-γ is much less expressed in muscle than adipose tissue, PPAR-γ is able to induce the expression of genes that regulate glucose uptake such as c-Cbl-associated protein (CAP), playing a role in glucose transporter-4 (GLUT4) translocation via the c-Cbl pathway [16]. Two independent groups generated mouse models with muscle-specific ablation of PPAR-γ using the cre-loxP recombination system with cre expression under the control of the muscle creatinine kinase promoter [17,18]. Both models show insulin resistance but mechanistically these studies are contradictory. Norris et al. [18] report impaired suppression of hepatic glucose production with normal glucose disposal into muscle, whereas Hevener et al. [17] shows an 80% impairment of glucose disposal in skeletal muscle in vivo and in vitro. Norris et al. [18] also report increased adiposity and obesity, despite a reduction in food intake. A pro-oxidative role for PPAR-γ has been suggested [19] and thus, disruption of PPAR-γ in muscle could impair lipid oxidation in this organ leading to a shunt of substrates towards other organs such as adipose tissue and liver. Disruption of muscle-derived PPAR-γ is shown here to affect lipid metabolism and glucose homoeostasis, on the other hand agonism of PPAR-γ in skeletal muscle may directly increase glucose disposal in muscle to ultimately improve whole body glucose homoeostasis as demonstrated by Hevener et al. [17].

Liver-derived PPAR-γ regulates fat storage in an environment of excess lipid

Liver PPAR-γ disruption has been developed in several murine backgrounds by expressing cre-recombinase under the control of liver-specific albumin promoter. Matsusue et al. [20], showed that disrupted liver PPAR-γ in ob/ob (obese–hyperglycaemic mice) background prevented hepatic triacylglycerol deposition. However, these mice had a worsened serum lipid profile and were insulin resistant. Gavrilova et al. [21] disrupted PPAR-γ in the liver of lipoatrophic, A-Zip/F-1 mice. Ablation of PPAR-γ in liver in lipoatrophic mice resulted in decreased accumulation of fat in liver and increased serum lipids, impaired triacylglycerol clearance and muscle insulin resistance [21]. PPAR-γ liver knockout mice respond to TZD treatment, whereas PPAR-γ liver knockouts in lipodystrophic mice do not, suggesting that adipose tissue-derived PPAR-γ primarily mediates the insulin-sensitizing effects of TZDs. Taken together, these results suggest that liver PPAR-γ plays an important role in lipid homoeostasis, in particular in lipid uptake and lipogenesis in liver when lipids are in excess, thus protecting other insulin-sensitive organs from lipid exposure that can induce the development of insulin resistance.

PPAR-γ is important for β-cell proliferation in response to high-fat feeding

There are evidence that PPAR-γ is expressed in β-cells [22] and PPAR-γ activation could induce insulin secretion in β-cells [23]. Ablation of PPAR-γ in β-cells had no effect on whole body glucose homoeostasis, despite alterations in islet morphology. In chow-fed animals the β-cell knockout mice had hyperplastic islets, yet on high fat diet the expected expansion of islets with obesity did not occur as in wt controls, possibly due to enhanced apoptosis [24]. This model provides evidence for a role of PPAR-γ in islet cell proliferation and the response of the β-cell to insulin demand associated with obesity and other insulin-resistant states.

Macrophage PPAR-γ can mediate anti-atherosclerotic effects

The generation of a macrophage PPAR-γ-specific knockout mouse [25] underlines the importance of this receptor in the regulation of key genes involved in cholesterol homoeostasis in macrophages through the ABC (ATP-binding-cassette) transporters. This observation strongly links macrophage PPAR-γ with the pathogenesis of atherosclerosis through its effects in foam-cell formation. Interestingly, when PPAR-γ null bone marrow is transplanted into atherosclerotic prone mice lacking the low-density lipoprotein receptor, these mice show a significant increase in atherosclerotic lesion size [26]. Although no alteration in glucose homoeostasis was reported by these authors, the emerging role of macrophages as a resident cell population in adipose tissue in the obese state [27], together with their capacity to produce inflammatory cytokines that can affect glucose homoeostasis, suggests that the metabolic phenotyping of these animals may reveal important findings.

Whole animal PPAR-γ impairment: isoform-specific knockouts and dominant negative mutations

Several mouse models with whole body impairment of PPAR-γ have been generated. This includes disruption of the adipose-specific isoform of PPAR-γ (PPAR-γ2) or knockin of dominant negative mutations in PPAR-γ. In contrast with tissue-specific ablation, the ablation of specific isoforms and knockin of dominant negative PPAR-γ mutations provide in vivo systems where impairment of PPAR-γ function can be evaluated in the context of whole body metabolic homoeostasis.

Isoform-specific regulation of metabolic homoeostasis

Two mouse models with ablation of PPAR-γ2 have been generated. The PPAR-γ2 knockout mice generated by Zhang et al. [28] presented with a marked lipodystrophy and signs of insulin resistance in male but not female animals, suggesting a gender-specific regulation of glucose homoeostasis through PPAR-γ2. Despite the presence of lipodystrophy, serum lipids were normal as was the lipid content in other tissues. Treatment with TZDs dramatically improved insulin sensitivity in these animals and thus PPAR-γ2 is not essential for TZDs’ insulin-sensitizing action. Our laboratory has also generated a mouse with selective disruption of PPAR-γ2 [29] and contrary to the model by Zhang et al. [28], we show that PPAR-γ2 ablation does not impair adipose-tissue development. Despite normal appearance of adipose tissue, the PPAR-γ2 knockout mice exhibit a certain degree of insulin resistance when fed a chow diet, suggesting a direct effect of PPAR-γ2 on insulin sensitivity that is independent of impaired adipose tissue development [29]. This insulin resistance is more pronounced in male mice and thus confirms that PPAR-γ2 regulates glucose homoeostasis in a sexually dimorphic way. Interestingly, high-fat feeding causes PPAR-γ2 adipocytes to become hypertrophic, yet does not worsen the insulin resistance of the PPAR-γ2 mice. Surprisingly, the change in adipocyte morphology on high-fat diet does not worsen high-fat diet-induced insulin resistance compared with high-fat-fed wt mice, raising the intriguing notion that PPAR-γ2 may be necessary for the development of adverse effect on carbohydrate metabolism, secondary to high-fat feeding.

Both Zhang et al. [28] and Medina-Gomez et al. [29] found that in vitro differentiation of adipocyte precursors is impaired. Considering that the adipose mass is not altered in these mice [29], we suspect that a robust compensatory mechanism occurs in vivo to conserve adipocyte differentiation. Our findings also suggest that the different PPAR-γ isoforms could have a different role and potency facing different physiological processes such as proliferation, differentiation or insulin sensitivity. Moreover, lipidomic analysis of PPAR-γ2 null adipose tissue has revealed an altered lipid content, and some of the lipid accumulated may serve as PPAR-γ ligands.

Ligand-binding domain PPAR-γ mutations, impaired lipid metabolism and vascular health

Another approach to further examine the consequences of universally impaired PPAR-γ function has been the generation of mouse lines carrying dominant negative mutations in the PPAR-γ gene. Tsai et al. [11] generated a mouse model harbouring the P465L (Pro465→Leu) amino acid substitution in PPAR-γ, the equivalent mutation previously identified in humans (P467L PPAR-γ) [2a]. The P465L PPAR-γ mutant animal recapitulates some of the human phenotypes as it displays hypertension and altered adipose tissue distribution. However, in contrast with the P467L PPAR-γ patients, the P465L PPAR-γ mouse develops normal amounts of adipose tissue and is insulin sensitive. Another dominant negative PPAR-γ (L466A) mouse model shows increased fatty acids, liver steatosis and develops mild insulin resistance, but only when fed a high-fat diet for as long as 8 months [30]. In these mutants blood pressure was elevated [11,30] underscoring the role of PPAR-γ in maintaining a normal vasculature function. Moreover, the finding that many of the metabolic abnormalities, classically associated with the metabolic syndrome, may coexist in the absence of insulin resistance point out a direct role of PPAR-γ in regulating fuel partitioning, lipid metabolism and vasculature function which is independent of the modulation of insulin sensitivity. The comparison of human and murine phenotypes suggest that insulin resistance associated with defective PPAR-γ function may only appear in the context of poorly differentiated or dysfunctional adipose tissue.

PPAR-γ plays a key role in the regulation of carbohydrate and lipid homoeostasis

Characterization of the PPAR-γ mouse models described above has provided important insights into the function of PPAR-γ but has also revealed a picture of complexity. It is clear that PPAR-γ plays a role in the development and maintenance of adipose tissue, and that it functions as an exquisite sensor of nutrients, able to regulate complex metabolic processes. These mouse models are useful in vivo systems to investigate the interplay between carbohydrate and lipid homoeostasis. Similarly, these mouse models have evidenced that adipose tissue expressed PPAR-γ as well as non-adipose tissue PPAR-γ contribute to this complex regulation of energy balance.

The study of these models has confirmed a key role of PPAR-γ in regulating physiological processes relevant to the pathologies of the metabolic syndrome. The fact that pathologies forming the spectrum of the metabolic syndrome can be present in the absence of insulin resistance, lead us to revise the hierarchical vision of this syndrome where insulin resistance is the key feature. Information obtained from these mouse models has been key to understanding the in vivo role of PPAR-γ and will contribute to future insights that will expand its therapeutic potential by allowing refinement of its pharmacological activation for the treatment of metabolic disorders such as the metabolic syndrome and diabetes.

Proteins in Disease: A Focus Topic at BioScience2005, held at SECC Glasgow, U.K., 17–21 July 2005. Edited by B. Austen (St George's Hospital Medical School, London, U.K.), C. Connolly (Dundee, U.K.), B. Irvine (Belfast, U.K.), M. Sugden (Queen Mary, London, U.K.) and V. Zammit (Hannah Research Institute, Ayr, U.K.).

Abbreviations

     
  • ATKO

    adipose tissue-specific knockout mice

  •  
  • NEFA

    non-esterified fatty acid

  •  
  • PPAR

    peroxisome-proliferator-activated receptor

  •  
  • TZD

    thiazolidinedione

  •  
  • wt

    wild-type

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